In human cancers, the PI3K/AKT/mTOR signaling pathways are commonly dysregulated, leading to increased cellular proliferation. The mTOR protein kinase forms 2 distinct complexes: TORC1 and TORC2. TAK-228 (formerly MLN0128) is an investigational, oral, highly selective, ATP-competitive inhibitor of TORC1/2 that may mitigate feedback activation within the PI3K/AKT/mTOR pathway. TORC1/2 inhibition may restore sensitivity to endocrine therapies in patients who have progressed on such agents plus everolimus, which primarily targets TORC1. This phase 2 study was designed to determine the recommended phase 2 dose (RP2D), as well as the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-228 plus exemestane or fulvestrant.

Overall, 24 women with a median age of 58.5 years (range, 33-75) were enrolled into phase 1b. For this study population, the median number of prior therapies was 5 (range, 1-10) and the median number of chemotherapy lines were 1 (range, 0-2). In part 1 (n = 12), patients were evenly split into TAK-228 plus exemestane or fulvestrant groups. No dose-limiting toxicities (DLTs) were seen, nor were any apparent differences in tolerability observed between groups. In part 2 (n = 12), 6 patients received 3-mg milled TAK-228 QD and no DLTs were seen. Of the 6 patients who received 4-mg milled TAK-228 QD, 1 patient treated with TAK-228 plus exemestane had DLTs of grade 3 nausea and diarrhea.

Of drug-related adverse events with grade 3 or higher, the most common (≥2 patients) were diarrhea (13%) and increased alanine aminotransferase, fatigue, hyperglycemia, nausea, rash, and stomatitis (each 8%).

Preliminary PK data from 11 patients suggested that there was a dose-related increase in total systemic exposure from 3 mg to 5 mg TAK-228, with no readily apparent difference between milled and unmilled TAK-228.

Overall, these data established the safety of milled TAK-228 at the RP2D of 4 mg QD plus exemestane or fulvestrant. No readily apparent or clinically meaningful differences were observed when TAK-228 was administered with either exemestane or fulvestrant. The preliminary efficacy shown in this study continues to be evaluated in the ongoing phase 2 portion.